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This study evaluates the safety and efficacy of AL3818 (anlotinib) hydrochloride in the treatment of metastatic or advanced alveolar soft part sarcoma (ASPS), leiomyosarcoma (LMS), and synovial sarcoma (SS). All participants with ASPS will receive open-label AL3818. In participants with LMS or SS, AL3818 will be compared to IV dacarbazine. Two-thirds of the participants will receive AL3818, one-third of the participants will receive IV dacarbazine.

To determine ORR in subjects with ASPS, defined as percentage of subjects who achieve a Complete Response (CR) or Partial Response (PR) as best responses according to RECIST 1.1 as evaluated by a blinded independent radiological review (BICR).

Progression Free Survival (PFS) (LMS/SS) [ Time Frame: From time of randomization to the date of disease progression or death from any cause, up to 48 months ]

To compare PFS in subjects with LMS or SS randomized to AL3818 versus dacarbazine, defined a median number of months from the date of randomization until the first documented sign of disease progression or death due to any causes, whichever occurs earlier as evaluated by a blinded independent radiologic review (BICR).

Secondary Outcome Measures:

Duration of Response (DOR) (ASPS) [ Time Frame: Up to 48 months ]

To determine DOR in subjects with ASPS, defined as median number of months from date of first documented objective response until first documented sign of disease progression or death due to any causes

To compare ORR in subjects with LMS or SS randomized to AL3818 versus dacarbazine, defined as percentage of subjects who achieve a Complete Response (CR) or Partial Response (PR) as best responses according to RECIST 1.1 as evaluated by a blinded independent radiological review (BICR).

All subjects with ASPS will be assigned to the open-label AL3818 arm to receive 12 mg AL3818 capsules orally once daily in 21-day cycles (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21).

Drug: AL 3818

Anlotinib (AL3818) 12 mg orally administered once daily in 21-day cycles (14 days on treatment, 7 days off treatment)

Other Name: Anlotinib

Experimental: Indication B: LMS AL3818 Arm

Subjects with LMS will be randomized in a 2:1 ratio to receive either AL3818 or IV dacarbazine. Subjects randomized to AL3818 will receive 12 mg AL3818 capsules orally once daily in 21-day cycles (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21).

Drug: AL 3818

Anlotinib (AL3818) 12 mg orally administered once daily in 21-day cycles (14 days on treatment, 7 days off treatment)

Other Name: Anlotinib

Active Comparator: Indication B: LMS Dacarbazine Arm

Subjects with LMS will be randomized in a 2:1 ratio to receive either AL3818 or IV dacarbazine. Subjects randomized to IV dacarbazine will receive dacarbazine at a dose of 1000 mg/m^2 as a 20-120 minute IV infusion on Day 1 of each 21-day treatment cycle.

Drug: Dacarbazine

Dacarbazine 1000 mg/m2 as a 20-120 minute IV infusion on Day 1 of each 21-day treatment cycle

Other Name: DTIC

Experimental: Indication C: SS AL3818 Arm

Subjects with SS will be randomized in a 2:1 ratio to receive either AL3818 or IV dacarbazine. Subjects randomized to AL3818 will receive 12 mg AL3818 capsules orally once daily in 21-day cycles (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21).

Drug: AL 3818

Anlotinib (AL3818) 12 mg orally administered once daily in 21-day cycles (14 days on treatment, 7 days off treatment)

Other Name: Anlotinib

Active Comparator: Indication C: SS Dacarbazine Arm

Subjects with SS will be randomized in a 2:1 ratio to receive either AL3818 or IV dacarbazine. Subjects randomized to IV dacarbazine will receive dacarbazine at a dose of 1000 mg/m^2 as a 20-120 minute IV infusion on Day 1 of each 21-day treatment cycle.

Drug: Dacarbazine

Dacarbazine 1000 mg/m2 as a 20-120 minute IV infusion on Day 1 of each 21-day treatment cycle

Other Name: DTIC

Detailed Description:

APROMISS is a phase 3 study evaluating the safety and efficacy of AL3818 (anlotinib) hydrochloride in the treatment of metastatic or advanced alveolar soft part sarcoma (ASPS), leiomyosarcoma (LMS), and synovial sarcoma (SS). Population pharmacokinetics and exploratory exposure-response analyses will also be conducted in subjects receiving AL3818.

Indication A: 56 subjects with metastatic or advanced ASPS not amenable to surgical resection will receive open-label AL3818 at a dose of 12 mg once daily in 21-day cycles (14 days on treatment, 7 days off treatment) until disease progression (defined by RECIST version 1.1) ot unacceptable toxicity. The primary endpoint is objective response rate (ORR), secondary endpoint is duration of response (DOR).

Indication B: 68 subjects with metastatic or advanced LMS who have failed at least one prior line of approved therapy will be enrolled and randomized in a 2:1 ratio to receive either AL3818 (12 mg once daily in 21-day cycles) or IV dacarbazine until disease progression (defined by RECIST version 1.1) or unacceptable toxicity. Subjects randomized to dacarbazine will have the option to crossover and receive AL3818 at the time of documented disease progression. The primary endpoint is progression free survival (PFS), the secondary endpoint is objective response rate (ORR).

Indication C: 95 subjects with with metastatic or advanced SS who have failed at least one prior line of approved therapy, including first-line anthracycline-containing chemotherapy, will be enrolled and randomized in a 2:1 ratio to receive either AL3818 (12 mg once daily in 21-day cycles) or IV dacarbazine until disease progression (defined by RECIST version 1.1) or unacceptable toxicity. Subjects randomized to dacarbazine will have the option to crossover and receive AL3818 at the time of documented disease progression. The primary endpoint is progression free survival (PFS), the secondary endpoint is objective response rate (ORR).

Eligibility

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Written informed consent provided before any study-specific procedures are initiated. Subject must be able to understand and be willing to sign a written informed consent form.

Show objective disease progression after the last administration of the last standard therapy or have stopped standard therapy due to intolerability (excluding ASPS subjects who have not received prior therapy) within 6 months of enrollment.

Has measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by CT or MRI scan within 28 days prior to enrollment.

Life expectancy of at least 3 months.

Females of childbearing potential must have a negative pregnancy test (by serum beta-HCG) within 7 days prior to the start of treatment.

Female of childbearing potential must be surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation), abstinent (at the discretion of the investigator), or agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last study drug administration. Females of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 2 years. - Males must agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last study drug administration. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) at the discretion of the investigator.

Adequate hematologic, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:

Total bilirubin < the upper limit of normal (ULN)

Alanine aminotransferase and aspartate aminotransferase < 2.5 of the ULN (< 5 x of ULN for subjects with liver involvement of their cancer)

International normalize ratio (INR) and the partial thromboplastin time (PTT) < 1.5 x ULN. (Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of an underlying abnormality in coagulation parameters exists)

Spot urine must not show 1+ or more protein in urine or the subject will require a repeat urinalysis. If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1,000 mg per 24 hours.

b. Indication B- LMS: Prior treatment with or have known hypersensitivity to dacarbazine.

c. Indication C - SS: Prior treatment with or have known hypersensitivity to dacarbazine.

Previous or concurrent cancer that is distinct in primary site or histology from ASPS, LS, or SS within 5 years before enrollment except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta, Tis and T1).

Received last dose of systemic cytotoxic therapy, radiation therapy or therapy with any investigational product within 28 days of enrollment.

Prior treatment with extended-field radiotherapy within 28 days prior to enrollment or prior treatment with extended-field radiotherapy for evaluating tumor lesions within 14 days prior to enrollment.

Known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided that they are stable with no evidence of progression by imaging, and all neurologic symptoms have returned to baseline, and should not be using corticosteroids for at least 7 days prior to study treatment.

Cavitary tumors or tumors invading or abutting large blood vessels.

History of gastrointestinal perforation, abdominal fistula or intra-abdominal abscess within 6 months of enrollment.

Known history of bleeding disorders (e.g., von Willebrand disease or hemophilia).

Use of aspirin (>325 mg/day) within 10 days prior to the first dose of study treatment. The use of prophylactic therapeutic anti-coagulants are allowed provided that INR or aPTT are within therapeutic limits (according to the medical standard of the enrollment institution) and patient has been on a stable dose of anticoagulants for at least two weeks prior to the first dose of study treatment.

Serious non-healing wound, active ulcer, or unhealed bone fracture.

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment.

Clinical conditions affecting the intake and use of oral medications (e.g., inability to swallow, chronic diarrhea, and intestinal obstruction)

Females who are pregnant or are breast-feeding.

Concomitant treatment with strong inhibitors or inducers of CYP1A2, CYP3A4 or CYP3A5 or sensitive substrates with narrow therapeutic index (TI) of CYP3A4, CYP2C9 and CYP2C19 within 14 days prior to enrollment and during the study unless there was an emergent or life-threatening medical condition that required it.

Any medical intervention, condition or any other circumstance which in the opinion of the investigator or the sponsor's medical monitor, could compromise adherence to study procedures or study objectives.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03016819